The present invention relates to a pharmaceutical preparation for implant in the field of ophthalmology, which utilizes a biodegradable polymer and has the property of gradually releasing a drug. More specifically, it relates to a controlled-release pharmaceutical preparation for intra-ocular implant to be applied after the surgical operation for disorders in retina/vitreous body or for glaucoma, which is produced by homogeneously dispersing an anti-inflammatory agent or a cell proliferation antagonist in polylactic acid, a polymer which is biodegradable, and forming the mixture into a particular shape.
Because of surgical remedies including membrane excision and silicone oil tamponade, the outcome of treatment for proliferative vitreoretinopathy has been markedly improved. However, recurrence has been reported in many cases in 4 to 6 weeks after the operation where only a surgical treatment was conducted (Machemer, R. et al., Ophthalmology, 85, 584-593 (1978)). Therefore, a variety of experimental attempts have been made concerning nedical therapy for the prevention of recurrence after operation.
Thus, for example, intra-vitreous injection of steroids, 5-fluorouracil and the like has been found effective on proliferative vitreoretinopathy (Tano, Y. et al., An. J. Ophthalmol., 89, 131-136 (1980) and Blumenkranz, M. S. et al., An. J. Ophthalnol. 94, 458-467 (1982)), and it has also been reported that the effect of filtering operation for glaucoma can be maintained by controlling the healing of intraocular tissues by subconjunctival injection of 5-fluorouracil, which is conducted once a day during the 1st week and once every other day during the 2nd week after the operation, so as to allow the drug to be transported into the eyeball (Nakano et al., Rinsho Ganka, 43, 1929-1933 (1989)).
However, it has been known that the intravitreous simple injection of drugs such as steroids and 5-fluorouracil involves a risk of cause damage to intra-ocular tissues, depending upon the dose applied, due to the exposure of intra-ocular tissues to the highly concentrated drugs at a tine (Shinada et al, Acta Soc. Ophthalmol. Jpn., 93, 501-510 (1989)). Moreover, repeated subconjunctival injections after glaucoma operation will impose excessive pain, physical as well as psychological, on the patient.
In order to solve these problems, studies have been conducted, for example, about a certain form of pharmaceutical preparation in which a drug is contained in microsphere particles so as to keep, for a particular period of time, the intraocular concentration of the drug at the level required to manifest its effect (Moridera et al., Acta Soc. Ophthalmol. Jpn., 94, 508-513 (1990)). Moreover, steroids in suspension forms are also expected to have a similar effect.
However, when these pharmaceutical preparations are injected intra-ocularly, for example into the vitreous body, there is involved a high risk that the microsphere particles and suspension particles will, as foreign matters, contact with and be accumulated on the surface of tissues such as the lens capsule and the corneal endothelium or that the drugs eluted therefrom will be accumulated at a high level in the lens and the cornea, thereby causing severe side-effects such as opacification of these transparent tissues. Thus, their safety has not yet been established.
In such circumstances, there has been a great need for a safe pharmaceutical preparation form which will release drugs Gradually and continuously so as to make it possible to maintain the intra-ocular concentration of the drugs at a therapeutic level for a desired period of time after an intra-ocular single administration.
With this background, the inventors conducted an intensive study to develop a controlled-release pharmaceutical preparation for intra-ocular use. As a result, the inventors have found that these requirements are fulfilled by a pharmaceutical preparation for intra-ocular implant which is produced by homogeneously dispersing a drug in a biodegradable polylactic acid with a particular range of Mn (number-average molecular weight), and forming the mixture into a desired shape. Through the accumulation of further studies, the present invention has been accomplished.